Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Dec 8;12(12):2033.
doi: 10.3390/jpm12122033.

The Soluble Folate Receptor in Autism Spectrum Disorder: Relation to Autism Severity and Leucovorin Treatment

Richard E Frye  1   2 , Alison Lane  3   4 , Ashley Worner  3   4 , Brianna A Werner  5 , Patrick J McCarty  6 , Adrienne C Scheck  3   4 , Heidi L Collins  7 , Steven J Adelman  7 , Edward V Quadros  8 , Daniel A Rossignol  2   9
Affiliations

The Soluble Folate Receptor in Autism Spectrum Disorder: Relation to Autism Severity and Leucovorin Treatment

Richard E Frye et al. J Pers Med. .

Abstract

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder with life-long consequences that affects up to 1 in 44 children. Treatment with leucovorin (folinic acid), a reduced form of folate, has been shown to improve symptoms in those with ASD and folate pathway abnormalities in controlled clinical trials. Although soluble folate binding proteins (sFBPs) have been observed in the serum of some patients with ASD, the significance of this finding has not been studied. Here, we present a cohort of ASD patients with sFBPs. These patients had severe ASD and were medically complex. Using baseline controlled open-label methodology and standardized assessments, these patients were found to improve in both core and associated ASD symptoms with leucovorin treatment. No adverse effects were related to leucovorin treatment. This is the first report of the sFBPs in ASD. This study complements ongoing controlled clinical trials and suggests that leucovorin may be effective for children with ASD who are positive for sFBPs. Further, sFBPs might be important biomarkers for treatment response to leucovorin in children with ASD. This study paves the way for further controlled studies for patients with sFBPs.

Keywords: autism spectrum disorder; folinic acid; leucovorin; soluble folate receptor.

PubMed Disclaimer

Conflict of interest statement

E.V.Q. is the inventors on a US patent for the detection of FRAAs issued to the Research Foundation of the State University of New York, USA. H.L.C. and S.J.A. are affiliated with Vascular Strategies which performs the commercial assay. The other authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Change in the Social Responsiveness Scale (t-scores) over time with initiation of leucovorin for patients with soluble folate binding proteins: (A) Total Score, (B) Awareness, (C) Cognition, (D) Communication, (E) Motivation and (F) Mannerisms. Each color line represents a single patient.
Figure 2
Figure 2
Change in the Aberrant Behavioral Scale raw score over time with initiation of leucovorin for patients with soluble folate binding proteins: (A) Total Score, (B) Irritability, (C) Social Withdrawal, (D) Stereotypy, (E) Hyperactivity and (F) Inappropriate Speech. Each color line represents a single patient.
Figure 2
Figure 2
Change in the Aberrant Behavioral Scale raw score over time with initiation of leucovorin for patients with soluble folate binding proteins: (A) Total Score, (B) Irritability, (C) Social Withdrawal, (D) Stereotypy, (E) Hyperactivity and (F) Inappropriate Speech. Each color line represents a single patient.
See this image and copyright information in PMC

References

    1. Maenner M.J., Shaw K.A., Baio J., Washington A., Patrick M., DiRienzo M., Christensen D.L., Wiggins L.D., Pettygrove S., Jennifer G., et al. Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years—Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2016. MMWR Surveill Summ. 2020;69:1–12. doi: 10.15585/mmwr.ss6904a1. - DOI - PMC - PubMed
    1. Rossignol D.A., Frye R.E. A review of research trends in physiological abnormalities in autism spectrum disorders: Immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures. Mol. Psychiatry. 2012;17:389–401. doi: 10.1038/mp.2011.165. - DOI - PMC - PubMed
    1. Frye R.E., Rossignol D.A. Treatments for biomedical abnormalities associated with autism spectrum disorder. Front. Pediatr. 2014;2:66. doi: 10.3389/fped.2014.00066. - DOI - PMC - PubMed
    1. Frustaci A., Neri M., Cesario A., Adams J.B., Domenici E., Dalla Bernardina B., Bonassi S. Oxidative stress-related biomarkers in autism: Systematic review and meta-analyses. Free Radic. Biol. Med. 2012;52:2128–2141. doi: 10.1016/j.freeradbiomed.2012.03.011. - DOI - PubMed
    1. Mahmuda N.A., Yokoyama S., Huang J.J., Liu L., Munesue T., Nakatani H., Hayashi K., Yagi K., Yamagishi M., Higashida H. A Study of Single Nucleotide Polymorphisms of the SLC19A1/RFC1 Gene in Subjects with Autism Spectrum Disorder. Int. J. Mol. Sci. 2016;17:772. doi: 10.3390/ijms17050772. - DOI - PMC - PubMed

LinkOut - more resources